Minerals and methods for their production and use

ABSTRACT

Uniformly sized and shaped particles of metal salts are provided comprised of one or more metal cations in combination with one or more simple oxoacid anions and a general method for the controlled precipitation of said metal salts from aqueous solutions. The methods proceed via the in situ homogeneous production of simple or complex oxoacid anions in which one or more of the nonmetallic elements e.g. Group 5B and 6B (chalcogenides), and 7B (halides) comprising the first oxoacid anion undergo oxidation to generate the precipitant anionic species along with concurrent reduction of the nonmetallic element of a second, dissimilar oxoacid anion. The oxoacid anions are initially present in solution with one or more metal cations known to form insoluble salts with the precipitant anion.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of Applicant's application Ser. No.08/784,439, filed Jan. 16, 1997, now U.S. Pat. No. 5,939,039.

FIELD OF THE INVENTION

This invention relates to methods for the preparation of minerals,especially phosphorus containing minerals, to the minerals thus preparedand to methods for their use. In accordance with certain embodiments,minerals are provided which are novel in that they are, at once,substantially homogeneous and non-stoichiometric. They can be producedthrough novel, low temperature techniques which offer excellent controlof composition and morphology.

BACKGROUND OF THE INVENTION

There has been a continuing need for improved methods for thepreparation of mineral compositions, especially phosphorus-containingminerals. This long-felt need is reflected in part by the great amountof research found in the pertinent literature. While such interest andneed stems from a number of industrial interests, the desire to providematerials which closely mimic mammalian bone for use in repair andreplacement of such bone has been a major motivating force. Suchminerals are principally calcium phosphate apatites as found in teethand bones. For example, type-B carbonated hydroxyapatite[Ca₅(PO₄)_(3−x)(CO₃)_(x)(OH)] is the principal mineral phase found inthe body, with variations in protein and organic content determining theultimate composition, crystal size, morphology, and structure of thebody portions formed therefrom.

Calcium phosphate ceramics have been fabricated and implanted in mammalsheretofore in many different forms including as shaped bodies, incements and otherwise. Different stoichiometric compositions such ashydroxyapatite (HAp), tricalcium phosphate (TCP), and tetracalciumphosphate (TTCP), have all been employed to this end in an attempt tomatch the adaptability, biocompatibility, structure and strength ofnatural bone. Despite tremendous efforts directed to the preparation ofimproved calcium phosphate and precursor hydroxyapatite materials forsuch uses, significant shortcomings still remain.

Early ceramic biomaterials exhibited problems derived from chemical andprocessing shortcomings that limited stoichiometric control, crystalmorphology, surface properties, and, ultimately, reactivity in the body.Intensive milling and comminution of natural minerals of varyingcomposition was required, followed by powder blending and ceramicprocessing at high temperatures to synthesize new phases for use invivo.

A number of patents have issued which relate to ceramic biomaterials.Among these are U.S. Pat. No. 4,880,610, B. R. Constantz , “In situcalcium phosphate minerals—method and composition;” U.S. Pat. No.5,047,031, B. R. Constantz, “In situ calcium phosphate minerals method;”U.S. Pat. No. 5,129,905, B. R. Constantz, “Method for in situ preparedcalcium phosphate minerals;” U.S. Pat. No. 4,149,893, H. Aoki, et al,“Orthopaedic and dental implant ceramic composition and process forpreparing same;” U.S. Pat. No. 4,612,053, W. E. Brown, et al,“Combinations of sparingly soluble calcium phosphates in slurries andpastes as mineralizers and cements;” U.S. Pat. No. 4,673,355 E. T.Farris, et al, “Solid calcium phosphate materials;” U.S. Pat. No.4,849,193, J. W. Palmer, et al., “Process of preparing hydroxyapatite;”U.S. Pat. No. 4,897,250, M. Sumita, “Process for producing calciumphosphate;” U.S. Pat. No. 5,322,675, Y. Hakamatsuka, “Method ofpreparing calcium phosphate;” U.S. Pat. No. 5,338,356, M. Hirano, et al“Calcium phosphate granular cement and method for producing same;” U.S.Pat. No. 5,427,754, F. Nagata, et al., “Method for production ofplatelike hydroxyapatite;” U.S. Pat. No. 5,496,399, I. C. Ison, et al.,“Storage stable calcium phosphate cements;” U.S. Pat. No. 5,522,893, L.C. Chow. et al., “Calcium phosphate hydroxyapatite precursor and methodsfor making and using same;” U.S. Pat. No. 5,545,254, L. C. Chow, et al.,“Calcium phosphate hydroxyapatite precursor and methods for making andusing same;” U.S. Pat. No. 3,679,360, B. Rubin, et al., “Process for thepreparation of brushite crystals;” U.S. Pat. No. 5,525,148, L. C. Chow,et al., “Self-setting calcium phosphate cements and methods forpreparing and using them;” U.S. Pat. No. 5,034,352, J. Vit, et al.,“Calcium phosphate materials;” and U.S. Pat. No. 5,409,982, A. Imura, etal “Tetracalcium phosphate-based materials and process for theirpreparation.”

While improvements have been made in ceramic processing technologyleading to ceramic biomaterials with better control over startingmaterials and, ultimately, the final products, improved preparativemethods are still greatly desired. Additionally, methods leading tocalcium phosphate containing biomaterials which exhibit improvedbiological properties are also greatly desired despite the great effortsof others to achieve such improvements.

Accordingly, it is a principal object of the present invention toprovide improved minerals, especially phosphorus-containing minerals.

A further object of the invention is to provide methods for forming suchminerals with improved yields, lower processing temperatures, greaterflexibility and control of product formation, and the ability to giverise to minerals having improved uniformity, biological activity, andother properties.

Another object is to improve the yield and control of synthetic mineralformation processes.

Yet another object is to give rise to cement compositions useful in therepair or replacement of bone in orthopaedic and dental procedures.

A further object is to provide minerals which are both substantiallyuniform and which are non-stoichiometric.

Further objects will become apparent from a review of the presentspecification.

SUMMARY OF THE INVENTION

The present invention is directed to create new methods for thepreparation of minerals, especially phosphorus-containing minerals. Theinvention also gives rise to uniquely formed minerals, includingminerals having improved compositional homogeneity and to mineralshaving modified crystal structures. New minerals are also provided bythe invention, including “non-stoichiometric” minerals, which differfrom commonly found minerals, crystal structures which are found innature, and structures which have traditionally “allowed” ratios ofconstituent atoms in unit cells.

The new paradigm created by this invention requires a specification ofterms used in this invention. The general method starts from rawmaterials, which are described herein as salts, aqueous solutions ofsalts, stable hydrosols or other stable dispersions, and/or inorganicacids. The phases produced by the methods of this invention [RedoxPrecipitation Reaction (RPR) and HYdrothermal PRocessing (HYPR)] aregenerally intermediate precursor minerals in the physical form ofpowders, particulates, slurries, and/or pastes. These precursor mineralscan be easily converted to a myriad of mixed and pure mineral phases ofknown and, in some cases, as yet unidentified mineral stoichiometries,generally via a thermal treatment under modest firing conditionscompared to known and practiced conventional art.

The methods of the invention are energy efficient, being performed atrelatively low temperature, have high yields and are amenable to carefulcontrol of product purity, identity and quality. Employment asbiological ceramics is a principal use for the materials of theinvention, with improved properties being extant. Other uses of theminerals and processes of the invention are also within the spirit ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an aggregated physical structure of an RPR generated,multiphasic β-tricalcium phosphate (β-TCP)+type-B carbonated apatite(c-HAp) [β-Ca₃(PO₄)₂+Ca₅(PO₄)_(3−x)(CO₃)_(x)(OH)] prepared in accordancewith one embodiment this invention. The entire agglomerated particle isapproximately 10 μm, and the individual crystallites are typically lessthan about 1 μm and relatively uniform in particle size and shape.

FIG. 2 represents assembled monetite, CaHPO₄ particles formed from ahydrothermal precipitation in accordance with this invention. The entireparticle assemblage is typically about 30 μm and is comprised ofrelatively uniformly rectangular cubes and plate-like crystallites ofvarious sizes and aspect ratios.

FIG. 3 is an X-ray Diffraction (XRD) plot of RPR generated calciumphosphate precursor mineral heated to 100° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase monetite.

FIG. 4 is an X-ray Diffraction (XRD) plot of an RPR generated calciumphosphate precursor mineral heated to 300° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase monetite.

FIG. 5 is an X-ray Diffraction (XRD) plot of RPR generated calciumphosphate precursor mineral heated to 500° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphases β-tricalcium phosphate (β-TCP)[major phase]+calcium pyrophosphate(CaH₂P₂O₇) [minor phase].

FIG. 6 is an X-ray Diffraction (XRD) plot of RPR generated calciumphosphate precursor mineral heated to 500° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphases β-tricalcium phosphate (β-TCP) [major phase]+apatite(Ca₅(PO₄)₃(OH)) [minor phase].

FIG. 7 is an X-ray Diffraction (XRD) plot of RPR generated calciumphosphate precursor mineral, without added [CO₃]²⁻, heated to 500° C.for 1 hour. The peak position and relative intensities indicate thepresence of the crystal phases β-tricalcium phosphate (β-TCP)[majorphase]+apatite (Ca₅(PO₄)₃(OH)) [minor phase].

FIG. 8 is an X-ray Diffraction (XRD) plot of RPR generated calciumphosphate precursor mineral, with added [CO₃]²⁻, heated to 500° C. for 1hour. The peak position and relative intensities indicate the presenceof the crystal phases β-tricalcium phosphate (β-TCP)[majorphase]+apatite (Ca₅(PO₄)₃(OH)) [minor phase]. The spectrum shows asignificant difference in the intensity of the HAp peaks, as compared tothat in FIG. 7.

FIG. 9 depicts Fourier Transform Infrared (FTIR) spectra of calciumphosphate as used for FIG. 8, indicating the presence of [CO₃]²⁻vibrations, at 880, 1400, and 1450 cm⁻¹, and associated P—O, P═Ovibrations, at 540-610, 1100-1250 cm⁻¹ respectively. A second FTIR plot(lower plot) of the material of FIG. 7 is also depicted to show lack ofcarbonate peaks at 880 cm⁻¹.

FIG. 10 is an X-ray Diffraction (XRD) plot of RPR generated zincphosphate precursor mineral heated to 500° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase Zn₃(PO₄)₂.

FIG. 11 is an X-ray Diffraction (XRD) plot of RPR generated ironphosphate precursor mineral heated to 500° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase Graftonite [Fe₃(PO₄)₂].

FIG. 12 is an X-ray Diffraction (XRD) plot of RPR generated aluminumphosphate precursor mineral heated to 500° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase AlPO₄.

FIG. 13 is an X-ray Diffraction (XRD) plot of HYPR generated calciumphosphate precursor mineral heated to 500° C. for 1 hour. The peakposition and relative intensities indicate the presence of an as yetunidentified calcium phosphate crystal phase.

FIG. 14 is an X-ray Diffraction (XRD) plot of HYPR generated calciumphosphate precursor mineral heated to 500° C. for 1 hour. The peakposition and relative intensities indicate the presence of an as yetunidentified calcium phosphate crystal phase and minor amounts of HAp.

FIG. 15 is an X-ray Diffraction (XRD) plot of HYPR generated calciumphosphate precursor mineral heated to 500° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase monetite [CaHPO₄].

FIG. 16 is an X-ray Diffraction (XRD) plot of RPR and HYPR generatedcalcium phosphate precursor minerals, heated to 500° C. for 1 hour, andmixed as a cement. The peak position and relative intensities indicatethe presence of the crystal phase monetite CaHPO₄ mixed withβ-TCP+type-B, carbonated apatite (c-HAp)[β-Ca₃(PO₄)₂+Ca₅(PO₄)_(3−x)(CO₃)_(x)(OH)] crystallites.

FIG. 17A is an X-ray Diffraction (XRD) plot of RPR and HYPR generatedcalcium phosphate precursor minerals, heated to 500° C. for 1 hour. Thepeak position and relative intensities indicate the presence of thecrystal phase monetite, CaHPO₄, mixed with β-TCP+type-B, carbonatedapatite (c-HAp) [β-Ca₃(PO₄)₂+Ca₅(PO₃)_(3−x) (CO₃)_(x)(OH)] crystallites.

FIG. 17B is an X-ray Diffraction (XRD) plot of RPR and HYPR generatedcalcium phosphate precursor minerals, heated to 500° C. for 1 hour, andmixed into a cement. The peak position and relative intensities indicatethe presence of the crystal phase β-TCP+type-B, carbonated apatite(c-HAp) [β-Ca₃(PO₄)₂+Ca₅(PO₄)_(3−x) (CO₃)_(x)(OH)] crystallites.

FIG. 18A is an X-ray Diffraction (XRD) plot of RPR generated neodymiumphosphate precursor mineral heated to 500° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase neodymium phosphate hydrate [NdPO₄-0.5H₂O].

FIG. 18B is an X-ray Diffraction (XRD) plot of RPR generated neodymiumphosphate precursor mineral heated to 700° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase Monazite-Nd [NdPO₄].

FIG. 18C is an X-ray Diffraction (XRD) plot of RPR generated ceriumphosphate precursor mineral heated to 700° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase Monazite-Ce [CePO₄].

FIG. 18D is an X-ray Diffraction (XRD) plot of RPR generated yttriumphosphate precursor mineral heated to 700° C. for 1 hour. The peakposition and relative intensities indicate the presence of the crystalphase Xenotime [YPO₄].

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In accordance with the present invention, methods are provided forpreparing an intermediate precursor mineral of at least one metal cationand at least one oxoanion. These methods comprise preparing an aqueoussolution of the metal cation and at least one oxidizing agent. Thesolution is augmented with at least one soluble precursor anionoxidizable by said oxidizing agent to give rise to the precipitantoxoanion. The oxidation-reduction reaction thus contemplated isconventionally initiated by heating the solution under conditions oftemperature and pressure effective to give rise to said initiation. Inaccordance with preferred embodiments of the invention, theoxidation-reduction reaction causes at least one gaseous product toevolve and the desired intermediate precursor mineral to precipitatefrom the solution.

The intermediate precursor mineral thus prepared can be treated in anumber of ways. Thus, it may be heat treated in accordance with one ormore paradigms to give rise to a preselected crystal structure or otherpreselected morphological structures therein.

In accordance with preferred embodiments, the oxidizing agent is nitrateion and the gaseous product is a nitrogen oxide, generically depicted asNO_(x(g)). It is preferred that the precursor mineral provided by thepresent methods be substantially homogeneous. It is also preferred thatthe temperature reached by the oxidation-reduction reaction not exceedabout 150° C. unless the reaction is run under hydrothermal conditionsor in a pressure vessel.

In accordance with other preferred embodiments, the intermediateprecursor mineral provided by the present invention is a calciumphosphate. It is preferred that such mineral precursor comprise, inmajor proportion, a solid phase which cannot be identified singularlywith any conventional crystalline form of calcium phosphate. At the sametime, the calcium phosphate mineral precursors of the present inventionare substantially homogeneous and do not comprise a physical admixtureof naturally occurring or conventional crystal phases.

In accordance with preferred embodiments, the low temperature processesof the invention lead to the homogeneous precipitation of high puritypowders from highly concentrated solutions. Subsequent modest heattreatments convert the intermediate material to e.g. novel monophasiccalcium phosphate minerals or novel biphasic β-tricalcium phosphate(β-TCP)+type-B, carbonated apatite (c-HAp)[β-Ca₃(PO₄)₂+Ca₅(PO₄)_(3−x)(CO₃)_(x)(OH)] particulates.

In other preferred embodiments, calcium phosphate salts are providedthrough methods where at least one of the precursor anions is aphosphorus oxoanion, preferably introduced as hypophosphorus acid or asoluble alkali or alkaline-earth hypophosphite salt. For the preparationof such calcium phosphates, it is preferred that the initial pH bemaintained below about 3, and still more preferably below about 1.

The intermediate precursor minerals prepared in accordance with thepresent methods are, themselves, novel and not to be expected from priormethodologies. Thus, such precursor minerals can be, at once,non-stoichiometric and possessed of uniform morphology.

It is preferred in connection with some embodiments of the presentinvention that the intermediate precursor minerals produced inaccordance with the present methods be heated, or otherwise treated, tochange their properties. Thus, such materials may be heated totemperatures as low as 300° C. up to about 700° C. to give rise tocertain beneficial transformations. Such heating will remove extraneousmaterials from the mineral precursor, will alter its composition andmorphology in some cases, and can confer upon the mineral aparticularized and preselected crystalline structure. Such heattreatment is to temperatures which are considerably less than areconventionally used in accordance with prior methodologies used toproduce the end product mineral phases. Accordingly, the heat treatmentsof the present invention do not, of necessity, give rise to the commoncrystalline morphologies structures of monetite, dicalcium or tricalciumphosphate, tetracalcium phosphate, etc., but, rather, to new andunobvious morphologies which have great utility in the practice of thepresent invention.

In accordance with the present invention, the minerals formed hereby areuseful in a wide variety of industrial, medical, and other fields. Thus,calcium phosphate minerals produced in accordance with preferredembodiments of the present invention may be used in dental andorthopaedic surgery for the restoration of bone, tooth material and thelike. The present minerals may also be used as precursors in chemicaland ceramic processing, and in a number of industrial methodologies,such as crystal growth, ceramic processing, glass making, catalysis,bioseparations, pharmaceutical excipients, gem synthesis, and a host ofother uses. Uniform microstructures of unique compositions of mineralsproduced in accordance with the present invention confer upon suchminerals wide utility and great “value added.”

Improved precursors provided by this invention yield lower temperaturesof formation, accelerated phase transition kinetics, greatercompositional control, homogeneity, and flexibility when used inchemical and ceramic processes. Additionally, these chemically-derived,ceramic precursors have fine crystal size and uniform morphology withsubsequent potential for more closely resembling or mimicking naturalstructures found in the body.

Controlled precipitation of specific phases from aqueous solutionscontaining metal cations and phosphate anions represents a difficulttechnical challenge. For systems containing calcium and phosphate ions,the situation is further complicated by the multiplicity of phases thatmay be involved in the crystallization reactions as well as by thefacile phase transformations that may proceed during mineralization. Thesolution chemistry in aqueous systems containing calcium and phosphatespecies has been scrupulously investigated as a function of pH,temperature, concentration, anion character, precipitation rate,digestion time, etc. (P. Koutsoukos, Z. Amjad, M. B. Tomson, and G. H.Nancollas, “Crystallization of calcium phosphates. A constantcomposition study,” J. Am. Chem. Soc. 102: 1553 (1980); A. T. C. Wong.and J. T. Czernuszka, “Prediction of precipitation and transformationbehavior of calcium phosphate in aqueous media,” in Hydroxyapatite andRelated Materials, pp 189-196 (1994), CRC Press, Inc.; G. H. Nancollas,“In vitro studies of calcium phosphate crystallization,” inBiomineralization—Chemical and Biochemical Perspectives, pp 157-187(1989)).

Solubility product considerations impose severe limitations on thesolution chemistry. Furthermore, methods for generating specific calciumphosphate phases have been described in many technical articles andpatents (R. Z. LeGeros, “Preparation of octacalcium phosphate (OCP): Adirect fast method,” Calcif. Tiss. Int. 37: 194 (1985)). As discussedabove, none of this aforementioned art employs the present invention.

Several sparingly soluble calcium phosphate crystalline phases, socalled “basic” calcium phosphates, have been characterized, includingalpha- and beta-tricalcium phosphate (α-TCP, β-TCP, Ca₃(PO₄)₂),tetracalcium phosphate (TTCP,Ca₄(PO₄)₂O), octacalcium phosphate (OCP,Ca₄H(PO₄)₃.-nH₂O, where 2<n<3), and calcium hydroxyapatite (HAp,Ca₅(PO₄)₃(OH)). Soluble calcium phosphate phases, so called “acidic”calcium phosphate crystalline phases, include dicalcium phosphatedihydrate (brushite-DCPD, CaHPO₄.H₂O), dicalcium phosphate anhydrous(monetite-DCPA, CaHPO₄), monocalcium phosphate monohydrate (MCPM,Ca(H₂PO₄)₂—H₂O), and monocalcium phosphate anhydrous (MCPA, Ca(H₂PO₄)₂).These calcium phosphate compounds are of critical importance in the areaof bone cements and bone grafting materials. The use of DCPD, DCPA,α-TCP, β-TCP, TTCP, OCP, and HAp, alone or in combination, has been welldocumented as biocompatible coatings, fillers, cements, and bone-formingsubstances ( F. C. M. Driessens, M. G. Boltong, O. Bermudez, J. A.Planell, M. P. Ginebra, and E. Fernandez, “Effective formulations forthe preparation of calcium phosphate bone cements,” J. Mat. Sci.: Mat.Med. 5: 164 (1994); R. Z. LeGeros, “Biodegradation and bioresorption ofcalcium phosphate ceramics,” Clin. Mat. 14(1): 65 (1993); K. Ishikawa,S. Takagi, L. C. Chow, and Y. Ishikawa, “Properties and mechanisms offast-setting calcium phosphate cements,” J. Mat. Sci.: Mat. Med. 6: 528(1995); A. A. Mirtchi, J. Lemaitre, and E. Munting, “Calcium phosphatecements: Effect of fluorides on the setting and hardening ofbeta-tricalcium phosphate—dicalcium phosphate—calcite cements,” Biomat.12: 505 (1991); J. L. Lacout, “Calcium phosphate as bioceramics,” inBiomaterials—Hard Tissue Repair and Replacement, pp 81-95 (1992),Elsevier Science Publishers).

Generally, these phases are obtained via thermal or hydrothermalconversion of (a) solution-derived precursor calcium phosphatematerials, (b) physical blends of calcium salts, or (c) natural coral.Thermal transformation of synthetic calcium phosphate precursorcompounds to TCP or TTCP is achieved via traditional ceramic processingregimens at high temperature, greater than about 800° C. Thus, despitethe various synthetic pathways for producing calcium phosphateprecursors, the “basic” calcium phosphate materials used in the art havegenerally all been subjected to a high temperature treatment, often forextensive periods of time. For the preparation of other “basic” calciumphosphate materials according to this invention, see also H. Monma, S.Ueno, and T. Kanazawa, “Properties of hydroxyapatite prepared by thehydrolysis of tricalcium phosphate,” J. Chem. Tech. Biotechnol. 31: 15(1981); H. Chaair, J. C. Heughebaert, and M. Heughebaert, “Precipitationof stoichiometric apatitic tricalcium phosphate prepared by a continuousprocess,” J. Mater. Chem. 5(6): 895 (1995); R. Famery, N. Richard, andP. Boch, “Preparation of alpha- and beta-tricalcium phosphate ceramics,with and without magnesium addition,” Ceram. Int. 20: 327 (1994); Y.Fukase, E. D. Eanes, S. Takagi, L. C. Chow, and W. E. Brown, “Settingreactions and compressive strengths of calcium phosphate cements,” J.Dent. Res. 69(12): 1852 (1990).

The present invention represents a significant departure from priormethods for synthesizing metal phosphate minerals in general, andcalcium phosphate powders in particular, in that the materials areprecipitated from homogeneous solution using a novel Redox PrecipitationReaction (RPR). They can be subsequently converted to TCP , HAp and/orcombinations thereof at modest temperatures and short firing schedules.Furthermore, precipitation from homogeneous solution (PFHS) inaccordance with this invention, has been found to be a means ofproducing particulates of uniform size and composition in a formheretofore not observed in the prior art.

The use of hypophosphite [H₂PO₂ ⁻] anion as a precursor to phosphate iongeneration has been found to be preferred since it circumvents many ofthe solubility constraints imposed by conventional calcium phosphateprecipitation chemistry and, furthermore, it allows for uniformprecipitation at high solids levels. For example, reactions can beperformed in accordance with the invention giving rise to productslurries having in excess of 30% solids. Nitrate anion is the preferredoxidant although other oxidizing agents are also useful.

The novel use of nitrate anion under strongly acidic conditions as theoxidant for the hypophosphite to phosphate reaction is beneficial fromseveral viewpoints. Nitrate is a readily available and an inexpensiveoxidant. It passivates stainless steel (type 316 SS) and is non-reactiveto glass processing equipment. Its oxidation byproducts (NO_(x)) aremanageable via well-known pollution control technologies, and anyresidual nitrate will be fugitive, as NO_(x) under the thermalconversion schedule to which the materials are usually subjected, thusleading to exceedingly pure final materials.

Use of reagent grade metal nitrate salts and hypophosphorus acid, aspracticed in this invention, will lead to metal phosphate phases ofgreat purity.

Methods for producing useful calcium phosphate-based materials areachieved by reduction-oxidation precipitation reactions (RPR) generallyconducted at ambient pressure and relatively low temperatures, usuallybelow 250° C. and preferably below 200° C., most preferably below 150°C. The manner of initiating such reactions is determined by the startingraw materials, their treatment, and the redox electrochemicalinteractions among them.

The driving force for the RPR is the concurrent reduction and oxidationof anionic species derived from solution precursors. Advantages of thestarting solutions can be realized by the high initial concentrations ofionic species, especially calcium and phosphorus species. It has beenfound that the use of reduced phosphorus compounds leads to solutionstability at ionic concentrations considerably greater than if fullyoxidized [PO₄]⁻³ species were used. Conventional processing art usesfully oxidized phosphorus oxoanion compounds and is, consequently,hindered by pH, solubility, and reaction temperature constraints imposedby the phosphate anion.

Typical reducible species are preferably nitric acid, nitrate salts(e.g. Ca(NO₃)₂.4H₂O), or any other reducible nitrate compound, which ishighly soluble in water. Other reducible species include nitrous acid(HNO₂) or nitrite (NO2⁻) salts.

Among the oxidizable species which can be used are hypophosphorus acidor hypophosphite salts (e.g. Ca (H₂PO₂)₂) which are highly soluble inwater. Other oxidizable species which find utility include acids orsalts of phosphites (HPO₃ ²⁻), pyrophosphites (H₂P₂O₅ ²⁻), thiosulfate(S₂O₃ ²⁻) , tetrathionate (S₄O₆ ²⁻²), dithionate (S₂O₄ ²) trithionate(S₃O₆ ²⁻), sulfite (SO₃ ²⁻), and dithionate (S₂O₆ ²⁻). In considerationof the complex inorganic chemistry of the oxoanions of Groups 5B, 6B,and 7B elements, it is anticipated that other examples of oxidizableanions can be utilized in the spirit of this invention.

The cation introduced into the reaction mixture with either or both ofthe oxidizing or reducing agents are preferably oxidatively stable (i.e.in their highest oxidation state). However, in certain preparations, orto effect certain reactions, the cations may be introduced in apartially reduced oxidation state. Under these circumstances, adjustmentin the amount of the oxidant will be necessary in order to compensatefor the electrons liberated during the oxidation of the cations duringRPR.

It is well known in the art that for solutions in equilibrium with ionicprecipitates, the solute concentrations of the reactant ions aredictated by solubility product relationships and supersaturationlimitations. For the Ca²⁺—[PO₄]⁻³ system, these expressions areexceedingly complicated, due in large part to the numerous pathways(i.e., solid phases) for relieving the supersaturation conditions.Temperature, pH, ionic strength, ion pair formation, the presence ofextraneous cations and anions all can affect the various solute speciesequilibria and attainable or sustainable supersaturation levels ( F.Abbona, M. Franchini-Angela, and R. Boistelle, “Crystallization ofcalcium and magnesium phosphates from solutions of medium and lowconcentrations,” Cryst. Res. Technol. 27: 41 (1992); G. H. Nancollas,“The involvement of calcium phosphates in biological mineralization anddemineralization processes,” Pure Appl. Chem. 64(11): 1673 (1992); G. H.Nancollas and J. Zhang, “Formation and dissolution mechanisms of calciumphosphates in aqueous systems,” in Hydroxyapatite and Related Materials,pp 73-81 (1994), CRC Press, Inc.; P. W. Brown, N. Hocker, and S. Hoyle,“Variations in solution chemistry during the low temperature formationof hydroxyapatite,” J. Am. Ceram. Soc. 74(8): 1848 (1991); G. Vereeckeand J. Lemaitre, “Calculation of the solubility diagrams in the systemCa(OH)₂—H₃PO₄—KOH—HNO₃—CO₂—H₂O,” J. Cryst. Growth 104: 820 (1990); A. T.C. Wong and J. T. Czernuszka, “Prediction of precipitation andtransformation behavior of calcium phosphate in aqueous media,” inHydroxyapatite and Related Materials, pp 189-196 (1994), CRC Press,Inc.; G. H. Nancollas, “In vitro studies of calcium phosphatecrystallization,” in Biomineralization—Chemical and BiochemicalPerspectives, pp 157-187 (1989)).

Additionally, while thermodynamics will determine whether a particularreaction is possible, kinetic effects may be very much more important inexplaining the absence or presence of particular calcium phosphatephases during precipitation reactions.

In the practice of certain preferred embodiments of this invention togive rise to calcium phosphates, soluble calcium ion is maintained atconcentrations of several molar in the presence of soluble hypophosphiteanion which is, itself, also at high molar concentrations. The solutionis also at a very low pH due to the presence of nitric andhypophosphorus acids. Indeed, such solutions of calcium andhypophosphite ions can be stable indefinitely, with respect toprecipitation, at room temperature or below. In contrast, it isimpossible (in the absence of ion complexation or chelating agents) tosimultaneously maintain calcium ions and phosphate anions at similarconcentrations as a solid phase would immediately precipitate to relievethe supersaturation. Upon oxidation of the hypophosphite ion tophosphite and, subsequently, to phosphate, calcium phosphate phases arerapidly precipitated from homogeneous solution under solution conditionsunique (concentration, pH, ionic strength) for the formation of suchmaterials. The combination of homogeneous generation of precipitatinganion, rapid precipitation kinetics, and unique thermodynamic regimeresults in the formation of calcium phosphate precursors having uniquesize and morphological characteristics, surface properties, andreactivities.

The foregoing consideration will also apply to minerals other than thecalcium phosphates. Per force, however, the phase diagram, equilibriumcondition and constituent mineral phases will differ in each family ofminerals.

Uniformly sized and shaped particles of metal salts comprised of one ormore metal cations in combination with one or more oxoacid anions canresult from the present general method for the controlled precipitationof said metal salts from aqueous solutions. These proceed via the insitu homogeneous production of simple or complex oxoacid anions of oneor more of the nonmetallic elements, Group 5B and 6B (chalcogenides),and 7B (halides). The first oxoacid anion undergoes oxidation (increasein chemical oxidation state) to generate the precipitant anionic speciesalong with concurrent reduction (decrease in chemical oxidation state)of the nonmetallic element of a second, dissimilar oxoacid anion, alloxoacid anions initially being present in solution with one or moremetal cations known to form insoluble salts with the precipitant anion.The metal cations are, preferably, oxidatively stable, but may, undergooxidation state changes themselves under certain conditions.

RPR is induced preferably by heating a homogeneous solution, so as topromote the onset and continuation of an exothermic redox reaction. Thisexothermic reaction results in the generation of gases, usually variousnitrogen oxide gases such as NO_(x), where 0.5<×<2, as the solublereduced phosphorus species are converted to precipitating anions whichthen homogeneously precipitate the calcium ions from the reactionmedium. At this stage, the reaction is essentially complete, resultingin an assemblage of ultrafine precipitated particles of thepredetermined calcium-phosphate stoichiometry. The reaction yield ishigh as is the purity of the reaction products.

Intermediate precursor mineral powders are homogeneously precipitatedfrom solution. Moderate heat treatments, temperatures<500° C., can beused to further the transformation to various phosphate containingphases. Proper manipulations of chemistry and process have led to mono-and multi phasic compounds with unique crystal morphologies [FIGS. 1 &2].

The nitrate/hypophosphite redox system involves a hypophosphiteoxidation to phosphate (P⁺¹ to P⁺⁵, a 4e⁻ oxidation) as depicted in thefollowing equations ( E_(o)/V from N. N. Greenwood and A. Earnshaw,“Oxoacids of phosphorus and their salts,” in Chemistry of the Elements,pp 586-595 (1984), Pergamon Press):

Reduction potential at pH 0, 25° C. Reaction E_(o)/V H₃PO₃+ 2H⁺ + 2e⁻ =H₃PO₂ + H₂O −0.499 (1) H₃PO₄+ 2H⁺ + 2e⁻ = H₃PO₃ + H₂O −0.276 (2) H₃PO₄+4H⁺ + 4e⁻ = H₃PO₂ + 2H₂O −0.775 Overall (3)

and a nitrate reduction to NO_(x) (N⁺⁵ to N⁺³ or N⁺², either a 2e⁻ or a3e⁻ reduction) as depicted in the following equations;

Reduction potential at pH 0, 25° C. Reaction E_(o)/V 2NO₃ ⁻ + 4H⁺ + 2e⁻= N₂O₄ + 2H₂O 0.803 (4) NO₃ ⁻ + 3H⁺ + 2e⁻ = HNO₂ + H₂O 0.94 (5) NO₃ ⁻ +4H⁺ + 3e⁻ = NO + 2H₂O 0.957 (6)

Chemical reactions are conveniently expressed as the sum of two (ormore) electrochemical half-reactions in which electrons are transferredfrom one chemical species to another. According to electrochemicalconvention, the overall reaction is represented as an equilibrium inwhich the forward reaction is stated as a reduction (addition ofelectrons), i.e.:

Oxidized species+ne ⁻=Reduced species

For the indicated equations at pH=0 and 25° C., the reaction isspontaneous from left to right if E_(o) (the reduction potential) isgreater than 0, and spontaneous in the reverse direction if E_(o) isless than 0.

From the above reactions and associated electrochemical potentials, itis apparent that nitrate is a strong oxidant capable of oxidizinghypophosphite (P⁺¹) to phosphite (P⁺³) or to phosphate (P⁺⁵) regardlessof the reduction reaction pathway, i.e., whether the reduction processoccurs according to Equation 4, 5, or 6. If an overall reaction pathwayis assumed to involve a combination of oxidation reaction (Eq.3) (4e⁻exchange) and reduction reaction (Eq.6) (3e⁻ exchange), one cancalculate that in order for the redox reaction to proceed to completion,4/3 mole of NO₃− must be reduced to NO per mole of hypophosphite ion toprovide sufficient electrons. It is obvious to one skilled in the artthat other redox processes can occur involving combinations of thestated oxidation and reduction reactions.

Different pairings of oxidation and reduction reactions can be used togenerate products according to the spirit of this invention. Indeed, theinvention generally allows for the in situ homogeneous production ofsimple or complex oxoacid anions in aqueous solution in which one ormore nonmetallic elements such as Group 5B and 6B (chalcogenides), and7B (halides) comprising the first oxoacid anion undergoes oxidation togenerate the precipitant anionic species along with concurrent reductionof the nonmetallic element of a second, dissimilar oxoacid anion.

In each of the above scenarios, the key is the reduction-oxidationreaction at high ionic concentrations leading to the homogenousprecipitation from solution of novel calcium phosphate powders. Neverbefore in the literature has the ability to form such phases, especiallycalcium-phosphate phases, been reported under the conditions describedin this invention.

The products can be adjusted by changing reaction conditions. Simplemodification of the anion mixture (i.e. inclusion of acetate ion) in thestarting solution can lead to a calcium phosphate phase withincorporated carbonate, which is most advantageous for in vivoconversion to bone, as bone itself is the carbonated version ofhydroxyapatite mineral, with the substitution of the carbonate occurringin the phosphate lattice position, thus termed type-B HAp. Otherbeneficial substitutions are derived from F, fluorine, substitutions,leading to fluorapatite, as desired in dentrifices and tooth enamel. Thesulfate anion may give rise to yet another beneficial calcium phase,whereby the hemihydrate species, CaSO₄-½H₂O, would provide an additionalsetting reaction when in contact with water, as with Plaster of Paris.Additional changes occur with the presence of other cations as dopantsor major components.

Specific embodiments of the invention utilize the aforementionedprocesses to yield unique calcium phosphate precursor minerals that canbe used to form a self-setting cement or paste. Once placed in the body,these calcium phosphate cements (CPC) will be resorbed and remodeled(converted) to bone. A single powder consisting of biphasic minerals ofvarying Ca/P ratio can be mixed to yield self-setting pastes thatconvert to type-B carbonated apatite (bone mineral precursor) in vivo.

The remodeling behavior of a calcium phosphate bioceramic to bone isdictated by the energetics of the surface of the ceramic and theresultant interactions with osteoclastic cells on approach to theinterface. Unique microstructures can yield accelerated reactivity and,ultimately, faster remodeling in vivo. The compositional flexibility inthe fine particles of this invention offers adjustable reactivity invivo. The crystallite size and surface properties of the resultantembodiments of this invention are more similar to the scale expected andfamiliar to the cells found in the body. Mixtures of powders derivedfrom the processes of this invention have tremendous utility as calciumphosphate cements (CPCs).

For example, calcium phosphate particles prepared in accordance withthis invention can be used in any of the orthopaedic or dentalprocedures known for the use of calcium phosphate; the procedures ofbone filling defect repair, oncological defect filling,craniomaxillofacial void filling and reconstruction, dental extractionsite filling, and potential drug delivery applications.

Numerous uses are anticipated. The oxidizing agents, reducing agents,ratios, co-reactants and other adducts, products and exemplary uses willbe understood by inorganic chemists from a review of the aforementionedchemical reactions. Calcium phosphates are indicated for biologicalrestorations, dental restorations, bioseparations media, and ion orprotein chromatography. Transition metal phosphates (Sc, Ti, V, Cr, Mn,Fe, Co, Ni, Cu, and Zn) have numerous potential uses as pigments,phosphors, catalysts, electromagnetic couplers, microwave couplers,inductive elements, zeolites, glasses, nuclear waste containment systemsand coatings. Addition of rare-earths phosphates can lead to uses asintercalation compounds, catalysts, glasses and ceramics,radiopharmaceuticals, pigments and phosphors, medical imaging agents,nuclear waste solidification, electro-optics, electronic ceramics, andsurface modifications.

Aluminum and zirconium phosphates are ideal candidates for surfaceprotective coatings, abrasive particles, polishing agents, cements, andfiltration products in either granular form or as coatings. The alkali(Na, K, Rb, Cs) and alkaline-earth (Be, Mg, Ca, Sr, Ba) phosphates wouldgenerate ideal low temperature glasses, ceramics, biomaterials, cements,glass to metal seals, and other numerous glass-ceramic materials, suchas porcelains, dental glasses, electro-optic glasses, laser glasses,specific refractive index glasses and optical filters.

EXAMPLES Example 1 Novel Low Temperature Calcium Phosphate PowderPreparation

An aqueous solution of 8.51 g 50 wt % hypophosphorus acid, H₃PO₂(Alfa/Aesar reagent #14142, CAS #6303-21-5), equivalent to 71.95 wt %[PO₄]⁻³ was combined with 8.00 g distilled water to form a clear,colorless solution contained in a 250 ml Pyrex beaker. To this solutionwas added 22.85 g calcium nitrate tetrahydrate salt, Ca(NO₃)₂.4H₂O (ACSreagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4)equivalent to 16.97 wt % Ca. The molar ratio of Ca/phosphate in thismixture was 3/2 and the equivalent solids level [as Ca₃(PO₄)₂] was 25.4wt %. Endothermic dissolution of the calcium nitrate tetrahydrateproceeded under ambient temperature conditions, eventually forming ahomogeneous solution. Warming of this solution above 25° C. initiated areaction in which the solution vigorously bubbled while evolvingred-brown acrid fumes characteristic of NO_(x(g)). The sample turnedinto a white, pasty mass which foamed and pulsed with periodic expulsionof NO_(x(g)). After approximately two minutes, the reaction wasessentially complete, leaving a white, pasty mass which was warm to thetouch. After cooling to room temperature, the solid (A) was stored in apolyethylene vial.

Three days after its preparation, a few grams of the damp, pasty solidwere immersed in 30 ml distilled water in order to “wash out” anyunreacted, water soluble components. The solid was masticated with aspatula in order to maximize solid exposure to the water. Afterapproximately 15 minutes, the solid was recovered on filter paper andthe damp solid (B) stored in a polyethylene vial.

X-ray diffraction (XRD) patterns were obtained from packed powdersamples using the Cu-Kα line (λ=1.7889 Angstrom) from a RigakuGeigerflex instrument run at 45 kV/30 mA using a 3 degree/minute scanrate over the 2θ angular range from 15-50° or broader. Samples were runeither as prepared or following heat treatment in air in either aThermolyne type 47900 or a Ney model 3-550 laboratory furnace. XRDresults are as follows (see FIGS. 3, 4, 5, and 6):

Heat Sample treatment Major phase Minor phase Unwashed (A) As preparedUndetermined — Unwashed (A) 300° C., 1 h Monetite [CaHPO₄] — Unwashed(A) 500° C., 1 h Whitlockite [β-Ca₃(PO₄)₂] CaH₂P₂O₇ Unwashed (A) 700°C., 1 h Whitlockite [β-Ca₃(PO₄)₂] + HAp[Ca₅(PO₄)₃(OH)] Washed (B) Asprepared Monetite [CaHPO₄] D.I. water Washed (B) 100° C., 1 h Monetite[CaHPO₄] D.I. water

Considerable amounts of NO_(x(g)) were evolved during firing of thesamples at or above 300° C.

Example 2 Novel Low Temperature Calcium Phosphate Powder Preparation

Example 1 was repeated using five times the indicated weights ofreagents. The reactants were contained in a 5½″ diameter Pyrexcrystallizing dish on a hotplate with no agitation. Warming of thehomogeneous reactant solution above 25° C. initiated an exothermicreaction which evolved red-brown acrid fumes characteristic ofNO_(x(g)). Within a few seconds following onset of the reaction, thesample turned into a white, pasty mass which continued to expelNO_(x(g)) for several minutes. After approximately five minutes, thereaction was essentially complete leaving a damp solid mass which washot to the touch. This solid was cooled to room temperature underambient conditions for approximately 20 minutes and divided into twoportions prior to heat treatment.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air, XRD indicatedthe fired solids to be composed of:

Sample Heat treatment Major phase Minor phase A 500° C., 1 h WhitlockiteHAp [Ca₅(PO₄)₃(OH)] [β-Ca₃(PO₄)₂] B 700° C., 1 h HAp [Ca₅(PO₄)₃(OH)]Whitlockite [β-Ca₃(PO₄)₂]

Example 3 Novel Low Temperature Calcium Phosphate Powder Preparation

An aqueous solution of 8.51 g 50 wt % H₃PO₂ was combined with 8.00 g of25.0 wt % aqueous solution of calcium acetate monohydrate,Ca(O₂CCH₃)₂.H₂O (ACS reagent, Aldrich Chemical Co., Inc. #40,285-0, CAS5743-26-0), equivalent to 5.69 wt % Ca, to give a clear, colorlesssolution contained in a 250 ml Pyrex beaker. To this solution was added20.17 g Ca(NO₃)₂.4H₂O salt. The molar ratio of Ca/phosphate in thismixture was 3/2 and the equivalent solids level [as Ca₃(PO₄)₂] was 27.3wt %. Endothermic dissolution of the calcium nitrate tetrahydrate saltproceeded giving a homogeneous solution once the sample warmed to roomtemperature. Further warming of this solution to >25° C. on a hotplateinitiated a reaction which proceeded as described in Example 1. Afterapproximately three minutes, the reaction was essentially completeleaving a moist, white, crumbly solid which was hot to the touch andwhich smelled of acetic acid. After cooling to room temperature, thesolid was stored in a polyethylene vial.

Heat treatment and X-ray diffraction analysis of this solid wereconducted as described in Example 1. Following heat treatment in air at500° C. for either 0.5 or 1 hour, XRD indicated the solid to be composedof whitlockite as the primary phase along with hydroxylapatite as thesecondary phase. XRD results indicate that the relative ratio of the twocalcium phosphate phases was dependent on the duration of the heattreatment and the presence of the acetate anion, but no attempts weremade to quantify the dependence.

Heated to 500° C., 1 h (Major) Whitlockite [β-Ca₃(PO₄)₂] (minor)Ca₅(PO₄)_(3-x)(CO₃)_(x)(OH)

Comparing the XRD spectra in FIG. 7 and 8 shows the difference in theamount of HAp-Ca₅(PO₄)_(3−x)(CO₃)_(x)(OH) phase present for each minorphase from Example 1 (which had no acetate) and Example 3 (acetatepresent), respectively. This is indicative of the counteranion effect oncrystal formation.

Fourier Transform Infrared (FTIR) spectra were obtained using a Nicoletinstrument (model number 5DXC ) run in the diffuse reflectance mode overthe range of 400 to 4000 cm⁻¹. The presence of the carbonated form ofHAp is confirmed by the FTIR spectra in FIG. 9 (400 to 1600 cm⁻¹), whichindicates the presence of peaks characteristic of [PO₄]⁻(580-600,950-1250 cm⁻¹) and of [CO₃]⁻² (880, 1400, & 1450 cm⁻¹). The P═O stretch,indicated by the strong peak at 1150-1250 cm⁻¹, suggests a structuralperturbation of hydroxyapatite by the carbonate ion.

Example 4 Colloidal SiO₂ added to calcium phosphate mixtures via RPR

An aliquot of 8.00 g 34.0 wt % SiO₂ hydrosol (Nalco Chemical Co., Inc.#1034A, batch #B5G453C) was slowly added to 8.51 g 50 wt % aqueoussolution of H₃PO₂ with rapid stirring to give a homogeneous, weaklyturbid colloidal dispersion. To this dispersion was added 22.85 gCa(NO₃)₂.4H₂O salt such that the molar ratio of calcium/phosphate in themixture was 3/2. Endothermic dissolution of the calcium nitratetetrahydrate proceeded giving a homogeneous colloidal dispersion oncethe sample warmed to room temperature. The colloidal SiO₂ was notflocculated despite the high acidity and ionic strength in the sample.Warming of the sample on a hotplate to >25° C. initiated a reaction asdescribed in Example 1. The resultant white, pasty solid was stored in apolyethylene vial.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for1.0 hour, XRD indicated the solid to be composed of whitlockite plushydroxyapatite.

Heated to 300° C., 2 h (Major) Calium pyrophosphate [Ca₂P₂O₇] (minor)Octacalcium phosphate [Ca₄H(PO₄)₃.2H₂O] Heated to 500° C., 1 h (Major)Whitlockite [β-Ca₃(PO₄)₂] (minor) HAp [Ca₅(PO₄)₃(OH)]

Example 5 Novel Low Temperature Calcium Phosphate Powder Preparation

Example 1 was repeated with the addition of 10.00 g dicalcium phosphatedihydrate, DCPD, CaHPO4.2H₂O (Aldrich Chemical Co., Inc. #30,765-3, CAS#7789-77-7) to the homogeneous solution following endothermicdissolution of the calcium nitrate salt. The DCPD was present both assuspended solids and as precipitated material (no agitation used).Warming of the sample to >25° C. initiated an exothermic reaction asdescribed in Example 1, resulting in the formation of a white, pastysolid. Heat treatment and X-ray diffraction of this solid were conductedas described in Example 1. Following heat treatment in air at 500° C.for 1 hour, XRD indicated the solid to be composed of whitlockite as theprimary phase along with calcium pyrophosphate (Ca₂P₂O₇) as thesecondary phase.

Heated to 500° C., 1 h (Major) Whitlockite [β-Ca₃(PO₄)₂] (minor) Ca₂P₂O₇

Example 6 Novel Low Temperature Zinc Phosphate Powder Preparation

An aqueous solution of 8.51 g 50 wt % H₃PO₂ in 8.00 g distilled waterwas prepared as described in Example 1. To this solution was added 28.78g zinc nitrate hexahydrate salt, Zn(NO₃)₂.6H₂O (ACS reagent, AldrichChemical Co., Inc. #22,873-7, CAS #10196-18-6), equivalent to 21.97 wt %Zn. The molar ratio of Zn/phosphate in this mixture was 3/2 and theequivalent solids level [as Zn₃(PO₄)₂] was 27.5 wt %. Endothermicdissolution of the zinc nitrate hexahydrate proceeded giving ahomogeneous solution once the sample warmed to room temperature. Furtherwarming of this solution to >25° C. on a hotplate initiated a reactionin which the solution vigorously evolved red-brown acrid fumes ofNO_(x(g)). The reaction continued for approximately 10 minutes while thesample remained a clear, colorless solution, abated somewhat for aperiod of five minutes, then vigorously resumed finally resulting in theformation of a mass of moist white solid, some of which was veryadherent to the walls of the Pyrex beaker used as a reaction vessel. Thehot solid was allowed to cool to room temperature and was stored in apolyethylene vial.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for 1hour, XRD indicated the solid to be composed of Zn₃(PO₄)₂ (see FIG. 10).

Heated to 500° C., 1 h (Major) Zn₃(PO₄)₂

Example 7 Novel Low Temperature Iron Phosphate Powder Preparation

An aqueous solution of 17.50 g 50 wt % H₃PO₂ was combined with 15.00 gdistilled water to form a clear, colorless solution contained in a 250ml Pyrex beaker on a hotplate/stirrer. To this solution was added 53.59g ferric nitrate nonahydrate salt, Fe(NO₃)₃-9H₂O (ACS reagent,Alfa/Aesar reagent #33315, CAS #7782-61-8), equivalent to 13.82 wt % Fe.The molar ratio of Fe/phosphate in this mixture was 1/1 and theequivalent solids level [as FePO₄] was 23.2 wt %. Endothermicdissolution of the ferric nitrate nonahydrate salt proceeded partiallywith gradual warming of the reaction mixture, eventually forming a palelavender solution plus undissolved salt. At some temperature >25° C., anexothermic reaction was initiated which evolved NO_(x(g)). This reactioncontinued for approximately 15 minutes during which time the reactionmixture became syrup-like in viscosity. With continued reaction, somepale yellow solid began to form at the bottom of the beaker. Afterapproximately 40 minutes of reaction, the sample was allowed to cool toroom temperature. The product consisted of an inhomogeneous mixture oflow density yellow solid at the top of the beaker, a brown liquid withthe consistency of caramel at the center of the product mass, and a sandcolored solid at the bottom of the beaker. The solids were collected asseparate samples insofar as was possible.

Heat treatment and X-ray diffraction of the solid collected from the topof the beaker were conducted as described in Example 1. Following heattreatment in air at 500° C. for 1 hour, XRD indicated the solid to becomposed of graftonite [Fe₃(PO₄)₂] plus some amorphous material,suggesting that the heat treatment was not sufficient to induce completesample crystallization (see FIG. 11).

Heated to 500° C., 1 h (Major) Graftonite [Fe₃(PO₄)₂]

Some mechanism apparently occurs by which Fe³⁺ was reduced to Fe²⁺.

Example 8 Novel Low Temperature Calcium Phosphate Powder Preparation

An aqueous solution of 19.41 g 50 wt % H₃PO₂ was combined with 5.00 gdistilled water to form a clear, colorless solution contained in a 250ml Pyrex beaker. To this solution was added 34.72 g Ca(NO₃)₂.4H₂O. Themolar ratio of Ca/phosphate in this mixture was 1/1 and the equivalentsolids level [as CaHPO₄] was 33.8 wt %. Endothermic dissolution of thecalcium nitrate tetrahydrate proceeded under ambient temperatureconditions, eventually forming a homogeneous solution once the samplewarmed to room temperature. Warming of this solution above 25° C.initiated a vigorous exothermic reaction which resulted in the evolutionof NO_(x(g)), rapid temperature increase of the sample to >100° C., andextensive foaming of the reaction mixture over the beaker rim,presumably due to flash boiling of water at the high reactiontemperature. After cooling to room temperature, the reaction product wascollected as a dry, white foam which was consolidated by crushing to apowder.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Results are as follows:

Heated to 300° C., 2 h (Major) Ca₂P₂O₇ (minor) Octacalcium phosphate[Ca₄H(PO₄)₃-2H₂O] Heated to 500° C., 1 h (Major) Ca₂P₂O₇

Example 9 Novel Low Temperature Calcium Phosphate Powder Preparation

Example 3 was repeated using ten times the indicated weights ofreagents. The reactants were contained in a 5½″ diameter Pyrexcrystallizing dish on a hotplate/stirrer. The reactants were stirredcontinuously during the dissolution and reaction stages. The chemicalreaction initiated by heating the solution to >25° C. resulted in theevolution of NO_(x(g)) for several minutes with no apparent effect onthe stability of the system, i.e. the solution remained clear andcolorless with no evidence of solid formation. After abating for severalminutes, the reaction resumed with increased intensity resulting in thevoluminous generation of NO_(x(g)) and the rapid appearance of a pastywhite solid material. The reaction vessel and product were both hot fromthe reaction exotherm. The product was cooled in air to a white crumblysolid which was stored in a polyethylene vial.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. foreither 0.5 or 1 hour, XRD indicated the solid to be composed ofwhitlockite as the primary phase along with hydroxyapatite as thesecondary phase. XRD results indicate that the relative ratio of the twocalcium phosphate phases was dependent on the duration of the heattreatment, but no attempts were made to quantify the dependence.

Heated to 500° C., 1 h (Major) Whitlockite [β-Ca₃(PO₄)₂] (minor)Ca₅(PO₄)_(3-x)(CO₃)_(x)(OH)

Example 10 Novel Low Temperature Aluminum Phosphate Powder Preparation

An aqueous solution of 10.82 g 50 wt % H₃PO₂ was combined with 2.00 gdistilled water to form a clear, colorless solution contained in a 250ml beaker. To this solution was added 30.78 g aluminum nitratenonahydrate salt, Al(NO₃)₃.9H₂O (ACS reagent, Alfa/Aesar reagent #36291,CAS #7784-27-2), equivalent to 7.19 wt % Al. The molar ratio ofAl/phosphate in this mixture was 1/1 and the equivalent solids level [asAlPO₄] was 22.9 wt %. Endothermic dissolution of the aluminum nitratenonahydrate proceeded giving a homogeneous solution once the samplewarmed to room temperature. Further warming of this solution to >25° C.on a hotplate initiated a reaction in which the solution vigorouslyevolved red-brown acrid fumes of NO_(x(g)). Reaction continued forapproximately 15 minutes during which the solution viscosity increasedconsiderably prior to formation of a white solid.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for0.5 hour, XRD indicated the solid to be composed of AlPO₄ plus someamorphous material, suggesting that the heat treatment was notsufficient to induce complete sample crystallization (see FIG. 12).

Example 11 Novel Low Temperature Calcium Phosphate Powder Preparation

An aqueous solution of 8.06 g 50 wt % H₃PO₂ reagent was combined with6.00 g distilled water to form a clear, colorless solution in a 250 mlPyrex beaker on a hotplate/stirrer. To this solution was added 19.23 gCa(NO₃)₂.4H₂O. The molar ratio of Ca/phosphate in this sample was 4/3and the equivalent solids [as octacalcium phosphate, Ca₈H₂(PO₄)₆-5H₂O]was 30.0 wt %. Endothermic dissolution of the calcium nitratetetrahydrate proceeded under ambient conditions, eventually forming ahomogeneous solution once the sample warmed to room temperature. Warmingof the solution above 25° C. initiated a vigorous exothermic reaction asdescribed in Example 1. After approximately three minutes, the reactionwas essentially complete leaving a moist, white, pasty solid.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for0.5 hour, XRD indicated the solid to be composed of whitlockite as theprimary phase along with hydroxyapatite as the secondary phase. Therewas no evidence for the formation of octacalcium phosphate (OCP),despite the initial sample stoichiometry. This result suggests that (a)alternate heat treatments are necessary to crystallize OCP and/or (b)excess Ca is present in the intermediate powder.

Heated to 500° C., 0.5 h (Major) Whitlockite [β-Ca₃(PO₄)₂] (minor) HApCa₅(PO₄)₃(OH)

Example 12 Novel Low Temperature Calcium Phosphate Powder Preparation

Example 11 was repeated except that no distilled water was used inpreparation of the reaction mixture. Warming of the homogeneous solutionabove 25° C. initiated an exothermic reaction as described in Example11. After approximately three minutes, the reaction was essentiallycomplete leaving a moist, pasty, white solid.

Heat treatment and X-ray diffraction of this solid were conducted asdescribed in Example 1. Following heat treatment in air at 500° C. for0.5 hour, XRD indicated the solid to be composed of calciumpyrophosphate (Ca₂P₂O₇).

Heated to 500° C., 0.5 h (Major) Ca₂P₂O₇

Example 13 Novel Low Temperature Hydrothermal (HYPR) Calcium PhosphatePowder Preparation

An aqueous solution of 50 wt % calcium nitrate tetrahydrate,Ca(NO₃)₂-4H₂O (ACS reagent, Aldrich Chemical Co., Inc. #23,712-4, CAS#13477-34-4) was prepared by dissolving 250.0 g of the salt in 250.0 gdistilled water. This solution was equivalent to 8.49 wt % Ca. A totalof 47.0 g of this solution was added, with rapid agitation, to anaqueous solution of 50 wt % sodium hypophosphite monohydrate,NaH₂PO₂—H₂O (Alfa/Aesar reagent #14104, CAS #10039-56-2) also preparedby dissolving 250.0 g of the salt in 250.0 g distilled water. The sodiumhypophosphite solution was equivalent to 44.80 wt % [PO₄]⁻³. The clear,colorless solution of calcium nitrate and sodium hypophosphite was thendiluted with 40.3 g distilled water. The molar ratio of Ca/phosphate inthis mixture was 5/3, and the equivalent solids level [as Ca₅(PO₄)₃(OH)(hydroxyapatite)] was 10.0 wt %. The sample was hydrothermally treatedusing a 300 cc volume stirred high pressure bench reactor (Model no.4561 Mini Reactor, Parr Instrument Co., Moline, Ill. 61265) equippedwith a temperature controller/digital tachometer unit (Model no. 4842,Parr Instrument Co.) and dial pressure gauge. All wetted parts of thereactor were fabricated from type 316 stainless steel. Ordinarily, type316SS is not the material of choice for inorganic acid systems such asthe solution precursors used in this invention, since phosphoric acidcan attack stainless steel at elevated temperatures and pressures.However, in the practice of this invention, direct contact (i.e.wetting) of the reactor surfaces was avoided through the use of a Pyrexglass liner. Only the stirrer and thermocouple sheath were immersed inthe reactant solutions and no corrosion was observed. In addition, it isassumed that the high nitrate ion concentration in the reactant mixtureprovided a passivating environment for the type 316SS.

One hundred grams (approximately 100 ml) of the calcium nitrate—sodiumhypophosphite solution was placed in the Pyrex liner of the reactor andthe intervening space between the glass liner and the reactor vessel wasfilled with distilled water to the level of the sample. This ensuredmaximum heat transfer to the sample since the reactor was externallyheated by an electric mantle. The approx. 100 ml sample volume leftsufficient head space in the reactor to accommodate solution expansionat elevated temperatures. The reactor was sealed by compression of aTeflon gasket. Heating of the reactor was performed at the maximum rateof the controller to a setpoint of 202° C. with constant stirring (500r.p.m.). The heating profile, as monitored by a thermocouple immersed inthe reactant mixture, was as follows:

REACTOR THERMAL PROFILE Time(min)  0  5  10  15  20  25  30  35  36Temp. 22 49 103 122 145 155 179 197 260 (° C.) (hold) (+/−2° C.)Pressure — — — — — — 160 210 220 (psi)

After holding at 200+/−3° C. for 12 minutes, the temperature rapidlyincreased to 216° C. with a resultant increase in reactor pressure toapproximately 330 psi. This exothermic event quickly subsided asevidenced by the rapid drop in reactor temperature to 208° C. within twominutes as the Parr reactor approached thermal equilibrium via anear-adiabatic process. After 15 minutes at 200° C., the reactor wasremoved from the heating mantle, quenched in a cold water bath, andopened after the head space was vented to ambient pressure.

A white precipitate was present in the glass liner. The solid wascollected by vacuum filtration on a 0.45 micron membrane filter(Millipore, Inc., Bedford, Mass., 01730), washed several times withdistilled water, and dried at approximately 55° C. in a forcedconvection oven. X-ray diffraction of this solid was conducted asdescribed in Example 1.

X-Ray diffraction results indicate a unique, unidentifiable diffractionpattern, see FIG. 13.

Example 14 Novel Low Temperature Hydrothermal (HYPR) Calcium PhosphatePowder Preparation

Example 13 was repeated except that 40.3 g of 1.0 M NaOH solution wasadded with rapid stirring to the homogeneous solution of calcium nitrateand sodium hypophosphite instead of the distilled water. This baseaddition resulted in the formation of a milk white dispersion,presumably due to precipitation of Ca(OH)₂.

The sample was hydrothermally processed as described in Example 13 withthe temperature setpoint at 207° C. The temperature ramp to 160° C. (25minutes) was as indicated for Example 13. At 30 minutes into the run, anexotherm occurred causing the temperature of the reaction mixture torise to a maximum of 221° C. within five minutes with a correspondingpressure increase to 370 psi. At 38 minutes into the experiment, thereactor was quenched to room temperature.

The reaction product consisted of a small amount of white precipitate.The material was collected as described in Example 13. X-ray diffractionof the dried sample was conducted as described in Example 1. XRD resultsindicated the solid to be comprised of the same unidentifiable pattern(crystal phase) found in Example 13 and minor amounts ofHAp-[Ca₅(PO₄)₃(OH)]. (see FIG. 14).

Example 15 Novel Low Temperature Hydrothermal (HYPR) Calcium PhosphatePowder Preparation

A total of 47.0 g of a 50 wt % aqueous solution of calcium nitratetetrahydrate was diluted with 53.0 g distilled water. Then, 6.00 gcalcium hypophosphite salt, Ca(H₂PO₂)₂ (Alfa/Aesar reagent #56168, CAS#7789-79-9), equivalent to 23.57 wt % Ca and 111.7 wt % [PO₄]⁻³, wasslurried into the Ca(NO₃)₂ solution using rapid agitation. An unknownamount of the calcium hypophosphite remained undissolved in the roomtemperature sample. The solubility behavior of Ca(H₂PO₂)₂ in theCa(NO₃)₂ solution at elevated temperatures is unknown. The molar ratioof Ca/phosphate in this system was 1.91.

This sample was hydrothermally processed as described in Example 13 withthe temperature setpoint at 212° C. The temperature ramp to 200° C. wasas indicated for Example 13. At 39 minutes into the run, an exothermoccurred causing the temperature of the reaction mixture to rise to amaximum of 252° C. within three minutes with a corresponding pressureincrease to 640 psi. At 44 minutes into the experiment, the reactor wasquenched to room temperature.

The reaction product appeared as a voluminous white precipitate plussome suspended solids. The material was collected as described inExample 13. X-ray diffraction of the dried solid was conducted asdescribed in Example 1. XRD indicated the solid to be monetite, CaHPO₄ ,see FIG. 15. The unique crystal morphology is depicted in the scanningelectron micrograph representation in FIG. 2.

Mixtures of the above described RPR and HYPR powders are useful in theformation of self-setting calcium phosphate cements for the repair ofdental and orthopaedic defects. The addition of specific components andsolubilizing liquids can also be added to form the precursor bonemineral constructs of this invention.

Example 16 Novel Cement Composition

Approximately 1.4 g of an alkaline solution (7 molar) formed using NaOHand distilled water, was mixed with 1.1 g of HYPR monetite [Example 15]and 1.1 g of RPR β-TCP-HAp(CO₃) [Example 3] in a glass mortar and pestlefor ˜45 seconds. After mixing, a smooth paste was formed, which wasscooped into a 3 ml polypropylene syringe and sealed for 20 minuteswithout being disturbed. Room temperature setting was observed after 20minutes, which was indicated by the use of a 454 gram Gilmore needle.The hardened cement was analyzed by X-ray diffraction which revealed aconversion to primarily type-B, carbonated apatite which is the desiredbone mineral precursor phase (see FIG. 16):

Cement XRD revealed (Major) Ca₅(PO₄)_(3-x)(CO₃)_(x)(OH) (minor)Whitlockite [β-Ca₃(PO₄)₂]

Example 17 Novel Cement Composition

A stock solution was formed with the approximately 7 M NaOH solutionused in Example 1 and 1.0% polyacrylic acid (PAA). PAA is used as achelating setting additive and wetting agent. The above solution wasused with several powder combinations to form setting cements. A 50/50powder mix of HYPR monetite [Example 15] and RPR β-TCP—HAp(CO₃) [Example3], approximately 0.7 g, was mixed with a glass spatula on a glass platewith 0.39 g of the 1% PAA-NaOH solution (powder to liquid ratio=1.73).The cement was extruded through a 3 ml syringe and was set after beingleft undisturbed for 20 minutes at room temperature (23° C.).

Examples 18-34

Powder/ Set Time (min.) Powder/ Gilmore Needle Liquid ratio (454 grams)Example Powder Liquid (Consistency) # = (1200 grams) 18 HYPR monetite +7M NaOH 1/1/1.2 <20 min RPR (Ex. 1) 500° C. Alkaline (slightly wet (#)Sol'n paste) 19 HYPR monetite 7M NaOH 1/1/1.2 <20 min (Ex. 15) +Alkaline (wet paste) (#) RPR (Ex. 1) 700° C. Sol'n 20 HYPR monetite 7MNaOH 1/1/1 15-18 min (Ex. 15) + Alkaline (sl. wet paste) −50 μm 45S5^(#)glass Sol'n 21 RPR (Ex. 1) 500° C. 7M NaOH 1.5/1 >40 min ‘neat’ Alkaline(wet paste) Sol'n 22 RPR (Ex.1) 300° C. 7M NaOH 1.7/1 40 min + Alkaline(sl. wet paste) RPR (Ex. 9) 500° C. Sol'n 23 HYPR monetite 7M NaOH1/1/1.4 No Set up to (Ex. 15) + Alkaline (v. gritty, wet) 24 hrs.Commercial β-TCP Sol'n 24 HYPR monetite 7M NaOH 1/1/1.4 20 min (Ex.15) + Alkaline (slightly wet (#) RPR (Ex. 2) 500° C. Sol'n paste) 25HYPR monetite 7M NaOH 1/1/1 <30 min (Ex. 15) + Alk. Sol'n + (claylikesl. set RPR (Ex. 2) 500° C. 20% PAA paste) 26 HYPR monetite 7M NaOH1/1/1 35 min. (Ex. 15) + Alk. Sol'n + (claylike RPR (Ex. 2) 500° C. 5%PAA paste) 27 HYPR monetite 7M NaOH 1/1/1.2 12-15 min (Ex. 15) + Alk.Sol'n + (slightly dry RPR (Ex. 11) 500° C. 1% PAA paste) 28 HYPRmonetite 10 wt % 1/1/1.2 1 hr 15 min (Ex. 15) + Ca(H₂PO₂)₂ (very wet RPR(Ex. 1) 500° C. (aq) paste) 29 RPR (Ex. 11) 500° C. 10 wt % 1.7/1 45 min‘neat’ Ca(H₂PO₂)₂ (very wet (aq) paste) 30 RPR (Ex. 11) 500° C. 10 wt %2.5/1 20 min ‘neat’ Ca(H₂PO₂)₂ (sl. dry (aq) paste/putty) 31 RPR (Ex.11) 500° C. 10 wt % 2.25/1 15 min ‘neat’ Ca(H₂PO₂)₂ + (very good 1 wt %paste/putty) H₂PO₂ (aq) 32 HYPR monetite 3.5M 1/1/1 35 min. (Ex. 15) +NaOH Alk. (good *12 min. RPR (Ex. 11) 500° C. Sol'n. paste/putty) 33HYPR monetite 3.5M 1/3/2 38 min. (Ex. 15) + NaOH Alk. (paste/putty) *15min. RPR (Ex. 11) 500° C. Sol'n. 34 HYPR monetite Saline, 1/1/1 43 min.(Ex. 15) + EDTA (good *20 min. RPR (Ex. 11) 500° C. bufferedpaste/putty) *= Set Time at 37° C., 98% Relative Humidity. HYPR monetite= HYdrothermally PRocessed monetite (CaHPO₄). RPR = Reduction-oxidationPrecipitation Reaction. 45S5^(#) glass = {24.5% CaO-24.5% Na₂O-6%P₂O₅-45% SiO₂ (wt %)}. PAA = Polyacrylic acid. Commercial β-TCP fromClarkson Chromatography Products, Inc. (S. Williamsport, PA)

. . .

Example 35 Novel Low Temperature Neodymium Phosphate Powder Preparation

An aqueous solution of 11.04 g of 50 wt. %H₃PO₂ was diluted with 5.00 gdistilled water to form a clear, colorless solution contained in a 250ml fluoropolymer resin beaker on a hotplate/magnetic stirrer. Added tothis solution was 36.66 g neodymium nitrate hexahydrate salt,Nd(NO₃)₃-6H₂O (Alfa/Aesar reagent #12912, CAS #16454-60-7), equivalentto 32.90 wt % Nd. The molar ratio of the Nd/P in this mixture was 1/1and the equivalent solids level (as NdPO₄) was 38 wt %. Endothermicdissolution of the neodymium nitrate hexahydrate salt proceeded withgradual warming of the reaction mixture, eventually forming a clear,homogeneous lavender solution at room temperature. Heating of thissolution with constant agitation to approximately 70° C. initiated avigorous endothermic reaction which resulted in the evolution ofNO_(x(g)) , rapid temperature increase of the sample to approximately100° C., and finally, formation of a pasty lavender mass. Heat treatmentof the pasty solid and subsequent X-ray diffraction analysis of thefired solid were conducted as described in Example 1. Results are asfollows (see FIGS. 18A & B):

Heated to 500° C., 45 min. (Major) Neodymium phosphate hydrate[NdPO₄-0.5H₂O] Heated to 700° C., 45 min. (Major) Monaazite-Nd [NdPO₄]

Example 36 Novel Low Temperature Cerium Phosphate Powder Preparation

An aqueous solution of 11.23 g of 50 wt. %H₃PO₂ was diluted with 5.00 gdistilled water to form a clear, colorless solution contained in a 250ml fluoropolymer resin beaker on a hotplate/magnetic stirrer. Added tothis solution was 36.94 g cerium nitrate hexahydrate salt, Ce(NO₃)₃-6H₂O(Johnson-Matthey reagent #11329-36), equivalent to 32.27 wt % Ce. Themolar ratio of the Ce/P in this mixture was 1/1 and the equivalentsolids level (as CePO₄) was 37.6 wt %. Endothermic dissolution of theneodymium nitrate hexahydrate salt proceeded with gradual warming of thereaction mixture, eventually forming a clear, homogeneous colorlesssolution at room temperature. Heating of this solution with constantagitation to approximately 65° C. initiated a vigorous endothermicreaction which resulted in the evolution of NO_(x(g)), rapid temperatureincrease of the sample to approximately >100° C., and finally, formationof a pasty light grey mass. Heat treatment of the pasty solid andsubsequent X-ray diffraction analysis of the fired solid were conductedas described in Example 1. Results are as follows (see FIG. 18C):

Heated to 700° C., 45 min. (Major) Monazite-Ce [CePO₄]

Example 37 Novel Low Temperature Yttrium Phosphate Powder Preparation

An aqueous solution of 14.36 g of 50 wt. %H₃PO₂ was diluted with 5.00 gdistilled water to form a clear, colorless solution contained in a 250ml fluoropolymer resin beaker on a hotplate/magnetic stirrer. Added tothis solution was 41.66 g yttrium nitrate hexahydrate salt, Y(NO₃)₃-6H₂O(Alfa/Aesar reagent #12898, CAS #13494-98-9), equivalent to 23.21 wt %Y. The molar ratio of the Y/P in this mixture was 1/1 and the equivalentsolids level (as YPO₄) was 32.8 wt %. Endothermic dissolution of theyttrium nitrate hexahydrate salt proceeded with gradual warming of thereaction mixture, eventually forming a clear, homogeneous colorlesssolution at room temperature. Heating of this solution with constantagitation to approximately 75° C. initiated a vigorous endothermicreaction which resulted in the evolution of NO_(x(g)), rapid temperatureincrease of the sample to approximately >100° C., and finally, formationof a pasty white mass. Heat treatment of the pasty solid and subsequentX-ray diffraction analysis of the fired solid were conducted asdescribed in Example 1. Results are as follows (see FIG. 18D):

Heated to 700° C., 45 min. (Major) Xenotime [YPO₄]

Example 38

A wide variety of minerals can be made in accordance with the thepresent invention. In the following two tables, oxidizing and reducingagents are listed. Any of the listed oxidants can be reacted with any ofthe listed reducing agents and, indeed, blends of each may be employed.Appropriate stoichiometry will be employed such that the aforementionedreaction is caused to proceed. Also specified are possible additives andfillers to the reactions. The expected products are given as are some ofthe expected fields of application for the products. All of thefollowing are expected generally to follow the methodology of some orall of the foregoing Examples.

Oxidizing Agents Reducing Agents Additives Product(s) Compounds of theform Oxoacids of Group 5B, 6B, Al₂O₃, ZrO₂, TiO₂, SiO₂, Ca(OH)₂,XY(PO₄), XY(SO₄), XNO₃, where X= and 7B, (where 5B includes N, DCPD,DCPA, HAp, TCP, TTCP, XY(PO₄)(SO₄), H, Li, Na, K, Rb, Cs, P, and As; 6Bincludes S, Se, MCMP, ZrSiO₄, W-metal, Fe metal, Ti WXYZ(PO₄)(SO₄)(CO₃),Cu, Ag, and Hg. and Te; 7B includes Cl, Br, metal, Carbon black, C-fiberor flake, WXYZ(PO₄)(SO₄)(CO₃)(F, Cl, Compounds of the form and I). CaF₂,NaF, carbides, nitrides, glass Br, I), WXYZ(PO₄)(SO₄) X(NO₃)₂, where X =Be, Phosphorous oxoacid fibers, glass particulate, glass- (CO₃)(F, Cl,Br, I)(OCl, OF, Mg, Ca, Sr. Ba, Cr, Mn, compounds: ceramics, aluminafibers, ceramic OBr, OI), in the form of fiber, Fe, Co, Ni, Cu, Zn, Rh,Hypophosphite (H₃PO₂); fibers, bioactive ceramic fibers and flake,whisker, granule, Pd, Cd, Sn, Hg, and Pb Hypophosphoric acidparticulates, polyacrylic acid, coatings, agglomerates and (H₄P₂O₆);polyvinyl alcohol, polymethyl- fine powders. Isohypophosphoric acidmethacrylate, polycarbonate, and other (H₄P₂O₆); stable polymericcompounds. Phosphonic acid or Acetates, formates, lactates, simplephosphorus acid (H₃PO₃); carboxylates, and simple sugars. Diphosphonicacid (H₄P₂O₅); Phosphinic acid or hypophosphorus acid (H₃PO₂). Compoundsof the form Sulfur oxoacid compounds: X(NO₃)₃, or XO(NO₃), Thiosulfuricacid (H₂S₂O₃); where X = Al, Cr, Mn, Dithionic acid (H₂S₂O₆); Fe, Co,Ni, Ga, As, Y, Polythionic acid (H₂S_(n+2)O₆); Nb, Rh, In, La, Tl, Bi,Sulfurous acid (H₂SO₃); Ac, Ce, Pr, Nd, Sm, Eu, Disulfurous acid(H₂S₂O₅); Gd, Tb, Dy, Ho, Er, Dithionous acid (H₂S₂O₄). Tm, Yb, Lu, U,and Pu Compounds of the form X(NO₃)₄ or XO(NO₃)₂, where X = Mn, Sn, Pd,Zr, Pb, Ce, Pr, Th, Th, Pa, U and Pu. Halogen oxoacids: perhalic acid(HOClO₃, HOBrO₃, HOIO₃); halic acid (HOClO₂, HOBrO₂, HOIO₂); halous acid(HOClO, HOBrO, HOIO)

The minerals prepared above may be used in a wide variety ofapplications. Exemplary of these applications are in pigments,phosphors, fluorescing agents, paint additives, synthetic gems,chromatography media, gas scrubber media, filtration media,bioseparation media, zeolites, catalysts, catalytic supports, ceramics,glasses, glass-ceramics, cements, electronic ceramics, piezoelectricceramics, bioceramics, roofing granules, protective coatings, barnacleretardant coating, waste solidification, nuclear waste solidification,abrasives, polishing agents, polishing pastes, radiopharmaceuticals,medical imaging and diagnostics agents, drug delivery, excipients,tabletting excipients, bioactive dental and orthopaedic materials andbioactive coatings, composite fillers, composite additives, viscosityadjustment additives, paper finishing additives, optical coatings, glasscoatings, optical filters, fertilizers, soil nutrient(s) additives.

What is claimed is:
 1. A substantially homogeneous calcium phosphatesalt that is an oxidation-reduction product formed by: preparing anaqueous solution comprising: a metal cation which is calcium; at leastone oxidizing agent; and at least one precursor anion oxidizable by saidoxidizing agent to form a phosphate; and heating said solution underconditions of temperature and pressure effective to initiate anoxidation-reduction reaction between said oxidizing agent and theprecursor anion; said reaction evolving at least one gaseous product;and giving rise to said phosphates said metal phosphate, saltprecipitating from said solution, and comprised of individualcrystallites having a crystal size of about 1 micron or below.
 2. Thecalcium phosphate salt of claim 1 having substantially uniformmorphology.
 3. The calcium phosphate salt of claim 1 having anon-stoichiometric composition.
 4. Substantially homogeneous, bioactiveand biocompatible calcium phosphate that is an oxidation-reductionproduct produced by: preparing an aqueous solution of a phosphorusoxoacid and a calcium nitrate; heating said solution to a temperature ofabout 250° C. or below under conditions of temperature and pressureeffective to initiate an oxidation-reduction reaction between theoxoacid and the calcium nitrate; said reaction evolving nitrogen oxidegas; and said calcium phosphate precipitating from said solution whereinsaid calcium phosphate is comprised of individual crystallites have acrystal size of about 1 μm or below.
 5. The calcium phosphate producedin accordance with claim 4 being further derived by heating to atemperature above about 100° C.
 6. The calcium phosphate produced inaccordance with claim 5 wherein said heating is to a temperature belowabout 700° C.
 7. The bioactive and biocompatible calcium phosphate ofclaim 4 wherein said phosphorus oxoacid is hypophosphorus acid.
 8. Abioactive cement for the repair of osseous defects comprising thebioactive and biocompatible calcium phosphate of claim
 4. 9. Thebioactive and biocompatible calcium phosphate of claim 4 admixed with apharmaceutically acceptable carrier or diluent.
 10. The bioactive andbiocompatible calcium phosphate of claim 4 admixed with a polymerizablematerial.
 11. An alkaline earth phosphate salt of an oxidation-reductionproduct formed by: preparing an aqueous solution comprising an alkalineearth cation; at least one oxidizing agent; and at least one precursoranion oxidizable by said oxidizing agent to form a phosphate; andheating said solution under conditions of temperature and pressureeffective to initiate an oxidation-reduction reaction between saidoxidizing agent and the precursor anion, said reaction evolving at leastone gaseous product; and giving rise to said phosphate, said alkalineearth metal phosphate salt precipitating from said solution wherein saidalkaline earth metal phosphate salt is substantially homogeneous and hasa substantially fine crystal size of about 1 μm or below, wherein saidalkaline earth metal is calcium.
 12. The alkaline earth metal phosphatesalt of claim 11 having a non-stoichiometric composition.